1. Field of the Invention
This invention relates to the synthesis of N-[N-(3,3-dimethylbutyl)-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester (neotame) by reductive alkylation and crystallization/isolation in methanol and water. This method of producing neotame results in high purity and is more simple and more economical than the typical preparation of neotame.
2. Related Background Art
N-[N-(3,3-dimethylbutyl)-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester (neotame) is a high potency dipeptide sweetener (about 8000.times. sweeter than sucrose) that has the formula ##STR1##
The chemical synthesis of neotame is disclosed in U.S. Pat. Nos. 5,480,668, 5,510,508, 5,728,862 and WO 00/15656, the disclosure of each of which is incorporated by reference herein.
U.S. Pat. No. 5,480,668 describes the formation of neotame in methanol, followed by methanol removal, formation of an aqueous hydrochloric acid solution of the neotame, filtration, drying and recrystallization from an ethanol/water mixture.
U.S. Pat. No. 5,510,508 describes the formation of neotame in aqueous acetic acid and methanol, followed by methanol removal, filtration, drying and washing.
U.S. Pat. No. 5,728,862 describes the formation of neotame in methanol, followed by filtration, washing, methanol reduction, addition of water, methanol distillation, filtration, washing and drying.
WO 00/15656 describes the formation of neotame using Z-aspartame (N-benzyloxycarbonyl-L-.alpha.-aspartyl-L-phenylalanine-1-methyl ester) in a methanolic solvent, followed by partial evaporation of the organic part of the solvent, optional addition of water before and/or during and/or after the partial evaporation of the organic part of the solvent, separation of the neotame formed and drying.
In addition to being complicated by various methanol removal and/or distillation steps, these chemical processes may produce several troublesome impurities, including N,N-di(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methyl ester (dialkylated aspartame), .alpha.-methyl hydrogen-3-( 3,3-dimethylbutyl)-2-L-(2,2-dimethylpropyl)-5-oxo-.alpha.-L-(phenylmethyl) -1,4(L)-imidazolidine diacetate (dialkylated imidazolidinone), N-[N-(3,3-dimethylbutyl)-L-.alpha.-aspartyl]-L-phenylalanine (demethylated .alpha.- or .beta.-neotame) and methyl ester of N-[N-(3,3-dimethylbutyl)-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester (methylated .alpha.- or .beta.-neotame). These impurities are represented respectively by the structural formulae: ##STR2## ##STR3##
Since neotame is mainly employed in foods for human consumption, it is extremely important that neotame exist in a highly purified state.
U.S. Pat. No. 5,728,862 outlines a purification method by which neotame is precipitated out of an aqueous/organic solvent solution, wherein the aqueous/organic solvent solution has an amount of organic solvent of about 17% to about 30% by weight.
Copending U.S. patent application Ser. No. 09/448,671, filed on Nov. 24, 1999, relates to methods of purifying neotame by crystallization in a variety of organic solvent/aqueous organic solvent mixtures. Each of these methods which uses an organic solvent and water mixture contemplates a solvent distillation step.
Thus, it is clear that there is a need to economically and efficiently produce pure N-[N-(3,3-dimethylbutyl)-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester.